The main objective of this investigation is to study the structural basis for the mutagenic and antimetabolite activities of selected purine and pyrimidine analogues, and to identify the structural roles that modified bases play in nucleic acids. The main emphasis is on the determinations of the crystal structures of purine and pyrimidine analogues, particularly halogenated pyrimidines and derivatives of thiopurine, in order to compare base stacking and hydrogen bonding interactions in these structures with those found for the natural bases. In addition, the project involves structural studies of bases that contain aliphatic groups, including bases that are produced by synthetic alkylating agents, and emphasis is on crystallographic studies of enzymes that are inhibited by purine and pyrimidine analogues. The ultimate aim is to identify the effects that various substituents exert on the structural properties of purines and pyrimidines, and to correlate these effects with the biological properties of the bases.